Lead (Pb), manganese (Mn) and arsenic (As) are common metal contaminants in the environment. They are of great public health concern because exposures to them impair neuronal functions, including adverse effects on neurodevelopment in children. Although epidemiological and animal studies have unequivocally established that these metals are neurotoxicants, the molecular mechanisms by which they impair neuronal funcfions remain poorly understood. Metal neurotoxicity is likely determined by intricate interactions between metals and their target cells. For instance, metals use cellular machinery to gain entry into target cells and to be transported to certain cellular sites; on the other hand, the target cells have intrinsic mechanisms to respond to metals and defend against metal toxicity. Critical to an ultimate mechanistic understanding of metal neurotoxicity, we believe, is discovering the cellular genes and pathways involved in metal toxicity and in the cellular responses to these insults. Accordingly, this proposal is designed to identify and characterize genes and genetic networks that mediate the neurotoxicity of Pb, Mn, and As. To this end, we will use a novel genome-wide gene inactivation approach together with a phenotype-based assay to identify human genes whose inacfivation alter neuronal susceptibility to metal exposure. We will then employ powerful bioinformatics tools to expand the isolated genes in the screen into genefic pathways and identify comprehensive biological networks that affect metal neurotoxicity. These analyses will be augmented by data mining of exisfing databases of metal toxicity. Finally, we will establish and characterize the physiological mechanisms through which the isolated genes affect the ability of metal exposure to dysregulate neuronal funcfions/status including synaptogenesis and neurite morphology.